A great deal of work has focused on synaptic plasticity and to the relation of synaptic plasticity to learning and memory. However, changes at the level of the synapse represent only one of several ways of modulating neurons. The input/output functions of a cell and the network to which it belongs also can be altered by changes in the other, nonsynaptic, properties of the neuron. In particular, the rhythmic firing properties of neurons can generate states which profoundly affect that cell's response to a given synaptic input. The recent cloning in our laboratory of genes (HCN-1 and HCN-2) encoding subunits of the Ih channel provides an opportunity to study the role of nonsynaptic mechanisms on both the dynamic and plastic properties of neurons and on the contribution of these properties to behavior. The Ih current contributes to nonsynaptic mechanisms because of its role in the "pacemaker" activity of neurons, enabling the cell to fire rhythmically, and by its ability to change the electrical properties of the membrane. Thus, a lesion of the molecular components of this current would be likely to change both the intrinsic firing properties of individual neurons and the rhythmic network oscillations (such as the theta rhythm) which impinge upon the neuron's response to synaptic input. With these goals in mind, we propose to generate whole animals and CA1-specific knockouts of these genes and to examine how HCN-1 and HCN-2 contribute to the theta rhythm of the hippocampus, to basic cellular and synaptic properties of the CA1 pyramidal cells, and to complex spike bursting and to LTP in these cells, as well as to hippocampal-based memory and to the properties of hippocampal place cells.